Stable granulates containing s-adenosylmethionine and process for preparation thereof

ABSTRACT

A fluid bed granulation process for manufacturing non-hygroscopic, stable granulates containing a water-soluble salt of S-adenosylmethionine is described. Said process comprises: a) the simultaneous, sequential or alternate dispersion of at least a solution of a water-soluble salt of SAMe (A) and of a solution of a coating agent (B), on a fluid bed granulation carrier (C) and b) the fluid bed granulation of the mixture. Granulates obtainable by said process and solid oral pharmaceutical forms obtainable by said granulates are disclosed.

This application is a continuation application which claims the prioritydate of the application entitled “Stable granules containings-adenosylmethionine and process for the preparation thereof” filed onMay 20, 2003 with application Ser. No. 10/432,338, which itself is a 371of PCT/EP02/13568, filed on Dec. 12, 2001. The disclosures of theseapplications are incorporated therein.

The present invention relates to a granulation process and, moreparticularly, it relates to a granulation process for preparing stablegranulates containing S-adenosylmethionine.

S-adenosylmethionine, in short SAMe, is a known compound of formula

broadly used in therapy, especially for its anti-inflammatory propertiesand in the treatment of chronic hepatic diseases (Merck Index, 1996, n.155).

It is generally prepared by fermentation and isolated as a salt, asdescribed for example in the U.S. Pat. No. 4,562,149.

The molecule is characterized by a significant intrinsic instability,mainly due to the intramolecular attack of the carboxylate ion onto themethylene in beta position, providing homoserine andmethylthioadenosine.

This high instability, that appears both in the solid state and as anaqueous solution at room temperature already, makes the isolation, thestorage and the formulation of the product particularly difficult.

In order to obviate to these problems of decomposition, many studieshave been undertaken and several solutions proposed.

First of all it was discovered that the salts of SAMe with bulky anionsare significantly more stable. Therefore many salts of SAMe, morestable, both water-soluble, such as sulfates, tosylates (U.S. Pat. No.4,562,149) or polymeric polycarboxylates (EP191133), and liposoluble,such as for example the long chain sulfosuccinates described in EP162324have been prepared.

Nevertheless the water-soluble salts of SAMe currently on the market,such as for example the disulfate tosylate or the 1,4-butandisulfonate,are extremely hygroscopic and/or sensitive to the moisture, thereforethey must be storage and processed under strictly controlledenvironmental conditions, with all the consequent economical andtechnological disadvantageous implications.

At present, the hygroscopic salts of SAMe are preserved and marketed inbulk as an anhydrous powder, prepared for example by lyophilization orspray-drying under strictly controlled temperatures, as described inEP141914, or in the pharmaceutical form of coated tablets. On thecontrary other pharmaceutical forms, such as for example capsules, morehandy and cheaper, are not practicable because rapidly damaged by thedehydrating action of the salt itself.

The instability of SAMe is accelerated, besides the heating, by anacidic medium too, hence the product, after administration, undergoes asignificant decomposition at gastric level with a consequent variableintestinal absorption and an uncertain therapeutical dosage. In thiscase, therefore, it becomes fundamental to protect the tablets with agastro-resistant coating, further increasing the production costs andterms.

As far as we know, because of all the above discussed problems, SAMe hasnever been formulated as a granulate.

We have now surprisingly found that the water-soluble salts of SAMe canbe granulated providing stable, non hygroscopic and, optionally,gastro-resistant granulates with a simple, cheap and industriallyapplicable process.

Those granulates are a very advantageous form for the storage and theadministration of the hygroscopic salts of SAMe and can be convenientlyused by direct compression, optionally with the addition of suitableexcipients, for manufacturing simple or coated non hygroscopic tabletsor directly used for filling capsules.

Another advantage of the granulates in object consists of thepossibility to formulate the SAMe together with other active drugs, inorder to produce stable and non hygroscopic pharmaceutical forms.

Finally, if the gastro-resisant granulate is directly used during thepreparation of tablets and capsules, it is possible to avoid the coatingstep or the use of special capsules, with significant saving of costsand time.

SUMMARY OF THE INVENTION

It is, therefore, an object of the present invention a process for themanufacture of granulates comprising a water-soluble salt ofS-adenosylmethionine which comprises:

a) the simultaneous, sequential or alternate dispersion of at least asolution of a water-soluble salt of SAMe (A) and of a solution of acoating agent (B), on a fluid bed granulation carrier (C) and

b) the fluid bed granulation of the mixture.

A second aspect of the invention is represented by the granulates,optionally gastro-resistant, obtainable by the above process.

A further object consists of solid oral pharmaceutical forms obtainablestarting from the above granulates and comprising said water-solublesalt of SAMe, alone or optionally associated with other active drugs.

Finally, the last aspect of the present invention consists of using saidgranulates for manufacturing oral compositions, for therapeutical orfeeding applications.

DESCRIPTION OF THE INVENTION

The granulation process object of the present invention is performed inclassical fluid bed dryers, in which the solutions, containing theactive drugs and the excipients, are sprayed onto the inert carrier anddried by a hot air flow.

Generally, in these devices, the rate of preparation of the granulatedepends on the flow, moisture and temperature of the air introduced intothe system, besides the speed of the addition of the solutions.

While it is possible to vary quite freely both the amount of the solventand the flow and moisture of the air, it is instead preferable to takeparticular care of the applied temperature.

In fact, due to the significant thermolability of the active drug, it isadvisable not to heat the product above 62° C., more preferably notabove 52° C. Generally it is preferable to operate at a temperaturebetween 48 and 52° C. and to complete the granulation by cooling themass, preferably with air or nitrogen.

With the aim to further reduce the risk of degradation of the activeproduct, it is possible to perform all the granulation procedure underan inert atmosphere, for example under nitrogen atmosphere.

Usable water-soluble salts of SAMe are the water-soluble salts stableenough under the process conditions. Sulfates, tosylates and1,4-butandisulfonates are preferred among the water-soluble, simple ormixed, salts in which the anions are particularly bulky. The disulfatetosylate of SAMe is especially preferred due to its solubility.Hereinafter, for the sake of conciseness, the water-soluble salts ofSAMe will be named as “salts of SAMe”.

The salt of SAMe, according to the present invention, is dissolved inthe selected solvent and, subsequently, dispersed onto the carrier.

Generally, being products for therapeutical or feeding use, it ispreferable to employ water as a favorite solvent. Nevertheless it ispossible to substitute the aqueous solvent, partially or completely,with other compatible solvents, provided that a good dissolution of theactive drug is achieved.

On this purpose, the addition of solubilizing agents or surfactants canbe considered.

The concentration of the solution of the salt of SAMe, preferably of itsaqueous solution, can vary according to several parameters. On the oneend the use of solutions too diluted is not advisable because itincreases the drying time and, consequently, the risk of productdegradation, on the other end it is necessary to stay under thesolubility limit of the product at the spraying temperature, in order toavoid the precipitation of solids that could obstruct the nozzles of thedevices. The solubility of the active drug depends on the salt, thesolvent, the temperature and the presence of other components optionallydissolved. In particular, in the case of aqueous solutions,concentrations of the salt of SAMe, preferably of the disulfatetosylate, between 10 and 25% by weight, more preferably between 15 and20%, are used.

With the aim to avoid the degradation of the compound, those aqueoussolutions are prepared at the time of use or prepared and kept at atemperature ranging from −15° C. to +4° C. and brought to the usetemperature, usually at about +15° C., just before use.

The granulation process of the present invention provides for thesimultaneous, sequential or alternate dispersion of the above solutionof the salt of SAMe (A) and of a solution of a coating agent (B).

Suitable coating agents according to the present invention, are organicpolymers able to swell and form an adhesive film such as, for example,chitins, carragenins, cellulose and chemically modified celluloses, gum,xanthane and others. Hydroxypropylmethylcelluloses, in particular thehydroxypropylcelluloses that, in a 2% by weight aqueous solution, show aviscosity comprised from 4000 to 15000 cPs, such as, for example, thosemarketed with the name of Pharmacoat and Methocel, are preferred coatingagents.

The concentration of coating agent in solution, preferably in theaqueous solution, is generally comprised from 5 to 15% by weight,preferably from 7 to 10%.

The granulation process, object of the present invention, provides forthe dispersion of the salt of SAMe (A) and the coating agent (B), onto acarrier for fluid bed granulation (C).

With the term “carrier for fluid bed granulation”, a pharmaceuticallyacceptable inert carrier, having the right granulometry, generally from50 to 500μ, preferably from 100 to 200μ, for use in fluid bed dryers,that allows the preparation of granulates suitable for storage andmarketing of the active drug, for the direct administration thereof orfor a subsequent formulation in form of capsules or tablets, is meant.

In particular, the final granulate, according to its use, shall have theright flowability and bulk density for filling capsules or the idealmechanical requirements for being compressed.

Starch, cellulose and maltodextrin can be named, as an example, amongthe carriers usable for preparing the granulates in object. In thepresent process microcrystalline cellulose is particularly advantageous,especially the cellulose marketed with the name of Vivapur 12® or PH101.

Carriers for granulation, according to the present invention, canoptionally contain water in a variable amount. As an example, in case ofmarketed microcrystalline cellulose, the percentage of water is about4%.

Preferably, in the granulation process according to the presentinvention, the amounts of the water-soluble salt of SAMe (A), of thecoating agent (B) and of the carrier (C) are such as to provide a finalgranulate that comprises up to 60% of the water-soluble salt of SAMe(A), from 5 to 15% of the coating agent (B) and from 25 to 45% of thecarrier (C) by weight with respect to the weight of the granulateitself, and even more preferably, from 48 to 55% by weight of (A).Besides the above mentioned components, that is the salt of SAMe (A),the coating agent (B) and the fluid bed granulation carrier (C), theprocess in object may provide for the addition of other pharmaceuticalexcipients. In fact, depending on the subsequent use of the granulate,the additional more suitable excipients and the ideal operatingconditions will be selected. Nevertheless, it is important to underlinethat those excipients are not directly responsible for the stability andnon-hygroscopicity of the granules, but only allow improving someparticular technological properties of the product.

As an example, when the granulate prepared according to the presentprocess is employed for compression, it can be advantageous to add asurfactant, in order to reduce the disintegration time of the finaltablets. Preferably the dispersion of the surfactant onto the granulateis performed at the end of the present granulation procedure.Surfactants suitable for that use are, as an example, the non-ionicsurfactants derived from sorbitane or other surfactants commonly used inpharmaceutical technology, among them lauryl sulfate and polysorbate 80are particularly suitable for the present granulation process.

With the aim to make the granulate gastro-resistant suitable coatingagents may be applied, preferably at the end of the present granulationprocess. In that case the gastro-resistant granulate will beadvantageously compressed or used for filling capsules, thus directlyproviding pharmaceutical forms suitable for the oral administration ofSAMe.

Suitable gastro-resistant coating substances are, for example, acrylicpolymers and lakes of Shellac type (Merck Index 13^(th) Ed. page 8557).In particular, copolymers of methacrylic acid with ethyl acrylate,commonly marketed with the name of Eudragit®, especially Eudragit L®,are preferably used.

A further example of additional pharmaceutical excipients usable for thepresent invention is represented by lubricants, such as magnesiumstearate, stearic acid, oils, hydrogenated fats, and by flowing agentssuch as talcum and silica, commonly used to improve the rheologicalproperties of powders and granulates in the preparation of solidformulations.

Silica, in particular the colloidal silica marketed as Aerosil 200®, isparticularly advantageous for the preparation, according to the presentinvention, of granulates employed for compression or filling ofcapsules.

In the granulation process of the present invention, depending on thesubsequent use of the granulate and the pharmaceutical form obtainedtherefrom, besides the excipients above mentioned, other commonly usedexcipients, such as, for example, sweeteners, e.g. saccharin, aspartame,cyclamate or similar, dyes, sparkling components, for example mixturesof tartaric acid and sodium bicarbonate, or flavoring agents, mayoptionally be used.

According to the granulation process of the present invention thedispersion of the solutions containing, respectively, the salt of SAMe(A) and the coating agent (B) and, optionally other additionalexcipients, may be simultaneous, sequential or alternate.

The conditions of the addition of the components and the duration of thespraying steps may vary depending on the kind of granulate wanted andits subsequent use. As an example, the simultaneous spraying of thesolution of SAMe (A) and of the coating agent (B) generally gives thegranulate a capillary protection, that makes it more resistant to theexposure to the air and, therefore, particularly suitable for fillingcapsules.

In such a case, the two components and the optional excipients, will bedissolved in separated solutions or, if chemically compatible, in thesame aqueous solution. In the case of a sequential dispersion, thesolution of the coating agent is sprayed only after the addition of thesolution of SAMe onto the carrier is finished. The resultant granulate,characterized by a superficial coating, quicker to be placed andcheaper, has very good breaking up capabilities that allow its directuse in preparing tablets.

Instead the alternate addition of the solution of SAMe (A) and of thecoating agent (B) allows the preparation of a granulate having astratified structure.

In such a case, by appropriately selecting the most suitable additionalexcipients, it is possible to prepare a slow or programmed releasegranulate usable, directly or after an additional formulation, for aless frequent oral administration of the active drug.

Regarding the conditions of addition of the other excipients optionallyused, it is preferable for example to disperse the gastro-resistantagent and the surfactant at the end of the spraying of the salt of SAMe,while the lubricant agent can be indifferently added at every step ofthe process, even at the beginning, that is directly onto thegranulation carrier.

In conclusion, the level of protection of the granulate preparedaccording to the present method depends on a set of elements such as theconditions of the addition of the components, the amount of the coatingagent used and the presence of other excipients. The optimization of thepreparation method of the granulate in object, depending on itsdestination, may be achieved by an appropriate modification of theprocess parameters up to now considered and, anyway, it is comprisedamong the common functions and capabilities of the man skilled in theart.

Another aspect of the invention is represented by the granulatesobtainable with the present process and by the pharmaceutical formsobtainable by the granulates themselves.

Those granulates may contain high amounts of the salt of SAMe andgenerally comprise up to 60% of the water-soluble salt of SAMe (A), from5 to 15% of the coating agent (B) and from 25 to 45% of the carrier (C)with respect to the weight of the granulate itself, even more preferablyfrom 48 to 55% by weight of (A). In addition, they may show a content ofresidual water generally comprised from 2 to 3% by weight, that usuallyis not detrimental to the stability of the salt of SAMe contained.

The granulate, prepared according to the process in object, ischaracterized by a bulk density usually comprised between 330 and 450g/l, appropriately modifiable depending on the destination of thegranulate itself.

That granulate may be simply assigned to the storage and marketing ofthe active drug or may be advantageously used for the preparation ofdifferent pharmaceutical forms. For example, depending on the additionalexcipients selected, the granulate may be useful for the preparation ofextemporary oral suspensions, optionally effervescent, of solid oralforms, such as effervescent, chewable or controlled-release tablets,including gastro-resistant tablets, or capsules. Generally, theoptimization of those formulations is among the normal capabilities andknowledge of the skilled in the field.

A further aspect of the present invention is represented bypharmaceutical compositions comprising a granulate of a hygroscopic saltof SAMe, prepared with the granulation method in object, in combinationwith one or more different active drugs.

In the literature, several examples of an associated use of SAMe withother active drugs are described, for example in the prevention andtreatment of the inflammation of the connective tissue (WO99/62524 eWO98/48816), of hepatic pain (WO99/43336) and in the inhibition of HIVreplication (EP827964 and DE19628514).

However, as far as we know, pharmaceutical compositions of SAMeassociated with other active drugs or nutriments do not exist on themarket, probably because of the low stability of the hygroscopic saltsof SAMe.

On the contrary those compositions can be advantageously realized byusing the stable and non hygroscopic granulate of SAMe of the presentinvention.

On that purpose the salt of SAMe and every other active drug selectedfor the association, can be granulated together according to the presentprocess, starting from a single solution or from separated solutions.Alternatively, in case of chemical incompatibility among the activedrugs, it will be possible to formulate in advance the salt of Sameaccording to the present invention and subsequently combined the soobtained granulate with the other active drugs under the most suitableform. As an example different granulates will be mixed and the resultantmixture will be used for extemporary oral preparations, formanufacturing tablets or for filling capsules.

According to a preferred embodiment of the granulation process of thepresent invention, the aqueous solutions of SAMe disulfate tosylate (A),of Pharmacoat 615 and, optionally, of Aerosil 200, are sprayed,simultaneously or successively, onto the microcrystalline cellulosecarrier in a fluid bed granulator and granulated, at a temperature nothigher than 52° C. and for the time needed for obtaining the desiredgranulate. Optionally, at the end of this preliminary phase, the aqueoussolutions containing Eudragit L or lauryl sulfate will be dispersed ontothe granulate and then the granulation is continued, at the idealtemperature and time. Finally, once the granulation step is finished,the air-cooling of the granulate is performed.

These and other aspects of the invention will be better illustrated bythe following examples and that, nevertheless, have not to be consideredlimiting of the invention itself.

EXAMPLES

Preparation of the Granulate

In the examples disclosed hereinafter the following materials anddevices, which can be substituted by equivalent materials or devices,were used:

Fluid bed dryers:

Hüttlin HKC-50-TJ

Glatt WST 30, vertically structured, with top spray, equipped withperistaltic pump. Bed volume: 94 l.

Water-soluble salts of SAMe:

-   -   S-adenosylmethionine disulfate tosylate (m.w. 766.8, Pliva)        Coating agents:    -   hydroxypropylmethylcellulose (Pharmacoat 615, Methocel E4M,        Methocel K15M Premium type)        Carriers for granulation:        Microcrystalline cellulose (Avicel PH101, Vivapur 12® type)        Maltodextrin (Cerestar)        Other excipients:    -   lubricants: colloidal silica (Aerosil 200 type)    -   surfactants: sodium lauryl sulfate, polisorbate 80    -   gastro-resistant coatings: acrylic and methacrylic polymers        (Eudragit L type)

Example 1

Preparation of a Granulate of SAMe, with the Addition of a Lubricant,(Simultaneous Spraying)

The 10% by weight aqueous solution of SAMe disulfate tosylate (250 Kg,corresponding to 25 Kg of salt of SAMe), kept at +4° C. and warmed up to15° C. before using, was transferred into a 300 liters stainless steelcontainer, equipped with a propeller mixer. Hydroxypropylmethylcellulose(HPMC, Pharmacoat 615) (5 Kg) and after mild stirring for 25′, silica(Aerosil 200) were added to the solution and the stirring was continuedfor other 15′ up to the complete dissolution of the components.

The solution was then sprayed for 13 hours onto Vivapur® 12microcrystalline cellulose (15 Kg), in a fluid bed granulator HüttlinHKC-50-TJ, in which the highest temperature of the outlet air was 49° C.At the end of the granulation the temperature of the product was 48° C.The granulate was then dried for 10′ more and cooled for 25′, with atemperature of the outlet air of 42° C.

The final granulate showed the following percent composition:Ingredients % (by weight) SAMe Disulfate Tosylate 54.3 Pharmacoat 61510.9 Aerosil 200 2.2 Vivapur ® 12 32.6 Total 100with a content of water equal to 2.42% w/w (loss on drying IR 105° C.for 15′) and a density of 420 g/l.

The yield of the granulation process was 95.43% (theoretical: 46.00 Kg,experimental 43.90 Kg).

Example 2

Preparation of a Granulate of SAMe (Sequential Spaying)

The 20.7% by weight aqueous solution of SAMe disulfate tosylate (75.7Kg, equal to 15.68 Kg of salt of SAMe), kept at −15° C. warmed up to 15°C. before using, was sprayed onto microcrystalline cellulose (14.852 Kg,PH101, humidity 4.25%) in a Glatt WST 30 fluid bed granulator, andgranulated for 8 hours and 40 min. at a maximum temperature of theoutlet air equal to 52° C. The final temperature of the product was 44°C. The granulated was coated with Pharmacoat 615 (0.632 Kg in a 7% byweight aqueous solution) in the same device, for 1 hour and 10 min. andthen cooled with air for 20′ (air outlet T after cooling 46° C.).

The final granulate showed the following percent composition:Ingredients % (by weight) SAMe Disulfate Tosylate 50.3 Pharmacoat 6152.0 PH101 47.7 Total 100with a content of water equal to 2.61% w/w (loss on drying IR 105° C.for 15′) and a density equal to 330 g/l.

The yield of the granulation process was 96.4% (theoretical: 31.16 Kg,experimental 30.04 Kg).

Example 3

Preparation of a Granulate of SAMe, with Addition of Lubricants(Sequential Spraying)

In this example, that is a variant of example 2, Aerosil 200 (0.9 Kg)was directly mixed with the carrier PH101 (13.5 Kg) before granulating.The mixture was then charged into the granulator and the fluid bedgranulation was performed, with the sequential addition of the salt ofSAMe (15 Kg of SAMe disulfate tosylate) and of the coating agent (0.6 Kgof Pharmacoat 615) under the same operating conditions described inexample 2.

The final granulate showed the following percent composition:Ingredients % (by weight) SAMe Disulfate tosylate 50.0 Pharmacoat 6152.0 Aerosol 200 3.0 PH101 45.0 Total 100

The presence of 3% of Aerosil 200 increased the flowability of the finalgranulate, improving the performance in tablet preparation.

Example 4

Preparation of a Granulate of SAMe for Filling Capsules.

In this example maltodextrin (12 Kg) instead of microcrystallinecellulose was used as a carrier, and then we went on according to theoperating conditions quoted in the example 2, starting from 15 kg ofSAMe disulfate tosylate and 0.9 Kg of Pharmacoat 615.

The final granulate showed the following percent composition:Ingredients % (by weight) SAMe Disulfate Tosylate 53.8 Pharmacoat 6153.2 Maltodextrin 43.0 Total 100

The presence of maltodextrin improved the performance of the granulatein the preparation of capsules. The granulate, in fact, showed a bulkdensity of 370 g/l and could contain a greater amount of the activedrug.

Example 5

Preparation of a Granulate for Compression

A batch of the final granulate, prepared according to the conditionsdescribed in example 1, by granulating an aqueous solution of SAMedisulfate tosylate (20 Kg of a 10% by weight aqueous solution), ofPharmacoat 615 (4 Kg), Aerosil 200 (0.8 Kg) and of Vivapur® 12 (12 Kg)was sprayed with an aqueous solution of lauryl sulfate (0.6 Kg dissolvedin 5 l of water) for 20′, under the same operating conditions used forexample 1.

The final granulate showed the following percent composition:Ingredients % (by weight) SAMe disulfate tosylate 53.5 Pharmacoat 61510.7 Aerosil 200 2.1 Vivapur ® 12 32.1 Lauryl sulfate 1.6 Total 100

The so obtained granulate was particularly suitable for the manufactureof tablets. The procedure herein described, could be repeated, in asimilar manner, starting from the final granulates prepared in theexamples 2, 3 and 4.

Example 6

Preparation of a Gastro-Resistant Granulate

A batch of a final granulate, prepared according to the examples 1, 2 or4, was coated with a gastro-resistant coating.

At the end of the granulation, an aqueous solution of Eudragit L wasdispersed onto the granulate and evaporated under conditions similar tothose already reported. The percentage of Eudragit, calculated on thefinal granulate, varied from 1.5 to 2.5% by weight.

The so obtained granulate was particularly suitable for fillingcapsules.

Stability Test on the Granulate

Example 7 (Comparison Example)

The test was performed by comparing the granulates prepared according tothe examples 1, 2, 3, 4, 5 and 6 with a reference mixture of powders(standard), the composition thereof corresponds to the medicinal productcontaining SAMe presently on the market (tablets SAMYR® by KnollPharmaceuticals containing 200 mg of SAMe disulfate tosylate).

The percent composition of the reference mixture is the following:Ingredients % (by weight) SAMe disulfate tosylate 53.2 D-mannitol 39.6Aerosil 200 2.7 Magnesium Stearate 1.8 Sodium Bicarbonate 2.7 Total 100

Samples of granulates, from the experiments 1, 2, 3, 4, 5 e 6 and fromthe reference mixture, were prepared by introducing 10 g. of the productin a polyethylene double bag and by sealing the bag itself, under normalatmosphere. For each product 12 samples were prepared and kept at a meantemperature of 25° C. and at a relative percentage of humidity equal to60%. The visual and instrumental (Karl-Fischer and HPLC) analysis of thesamples was performed every 2 weeks for a total time of 24 weeks, withthe following results:

SAMe Granulates Mean analytical parameters Week 0 Week 12 Week 24Appearance Cream colored In In granules compliance compliance Content ofwater (K.F.) (%) 2.5-3.5 3.0-3.5 3.5-4.5 Content of impurities 0.5-0.91.3-1.5 1.5-1.2 HPLC (methylthioadenosine %)

Reference Mixture Mean analytical parameters Week 0 Week 12 Week 24Appearance White powder Content of water (K.F.) (%) 1.0-1.5 Content ofimpurities HPLC 0.5-1.0 (methylthioadenosine %)

After 3-4 weeks only, in some cases even less, the samples of thereference mixture were no more comparable. In fact the powder became acrumbly and sticky solid mass, characterized by the typical unpleasantsmell of methylthioadenosine.

From the experiment it is evident that the granulates prepared accordingto the present process have characteristics of stability andnon-hygroscopicity clearly higher than the compositions of SAMecorresponding to those available on the market.

Preparation of Tablets and Capsules

Example 8

Preparation of Tablets

A sample for each granulate, prepared according to the examples 1, 2, 3and 5, was added with small amounts of D-mannitol and lubricating agentsand used for evaluating the performances of the mixture to directcompressing. The composition of the resultant mixture was the following:Ingredients amount (g) SAMe granulate 240 D-mannitol 15 Magnesiumstearate 4.5 Talc 3.0

The mixtures were prepared and compressed under normal atmosphere, at atemperature of 22-26° C. and with a relative humidity of 50-75%.

A Ronchi alternative machine with convex round punches (12.5 mm) wasused for the compression test by applying a pressure of 3-4 ton. Thetablets showed the following parameters: Parameter Measured value Meanweight 0.883 g (theoretical 0.875 g, S.D. 0.01619) Height 7.0-7.3 mmHardness (Schleuninger2E) 39-60 newtons Disgregation time pH 1 > 1 h pH6.8 < 1 h

The tablets did not have a gastro-resistant coating but, due to thespecial protection of the granulate, their performances corresponded tothose of coated tablets.

Example 9

Preparation of Tablets (Comparative Example)

A compression test under the same environmental conditions and with thesame machine of example 8 was performed, using as a mixture thereference mixture of powders described in the example 7.

After few minutes the reference product was too sticky to be handled andthe compressing machine was stopped in order to avoid damages to themechanical parts. In conclusion, the reference mixture, corresponding tothe compositions of SAMe currently on the market, is too hygroscopic tobe handled under standard atmosphere.

Example 10

Preparation of Capsules

A sample for each granulate prepared according to the example 4 and 6,was added with small amounts of lactose and lubricant agents and usedfor evaluating the performances of the mixtures in filling capsules ofthe Snap-fit kind. The composition of the resultant mixtures was thefollowing: Ingredients (mg) 00 Dimension 0 Dimension 1 Dimension SAMegranulate 400 25 150 lactose 50 30 50 Magnesium stearate 10 10 5 Talc 55 2 Total 465 295 207 Mean gross weight 585.3 390.2 288.5

The mixtures were prepared and used under standard atmosphere, at atemperature of 22-26° C. and with a relative humidity of 50-75%.

A compact kind MG2 encapsulating machine was used for the preparation ofcapsules. The capsules so obtained, due to the properties of thegranulates prepared according to the present method, were more stablethan those prepared by using salts of SAMe non-granulated according tothe process of the present invention.

Preparation of Associated Compositions.

The granulate of SAMe, due to its characteristics of stability, can beformulated together with other active drugs or nutriceuticals, for thepreparation of therapeutical, dietetic and/or integrator products, asillustrated in the following examples:

Example 11

Integrator Products for the Elders 500 mg Tablets SAMe Granulate (titre50%) mg. 200.0 Vitamin E (50%) mg. 10.0 Ginko biloba dried exctr. mg.20.0 Lactose mg. 200.0 Microcrystalline cellulose mg. 50.0 Talc mg. 10.0Magnesium stearate mg. 10.0

Example 12

Integrator Product for Enhancing the Hepatic Performance 500 mg TabletsSAMe Granulate (titre 50%) mg. 200.0 Vitamin B1 mg. 0.7 Thistle driedexctr. mg. 50.0 Lactose mg. 200.0 Microcrystalline cellulose mg. 50.0Talc mg. 10.0 Magnesium stearate mg. 10.0

1. A process for manufacturing granulates containing a water-solublesalt of S-adenosylmethionine characterized by comprising: a) thesimultaneous, sequential or alternate dispersion of at least a solutionof a water-soluble salt of SAMe (A) and of a solution of a coating agent(B), on a fluid bed granulation carrier (C) and b) the fluid bedgranulation of the mixture so obtained at a temperature not above 62° C.2. A process according to claim 1 wherein said fluid bed granulation isperformed at a temperature from 48 and 52° C.
 3. A process according toclaim 1 wherein the water-soluble salt of SAMe (A) is a salt of SAMe,simple or mixed, selected among sulfate, tosylate and1,4-butandisulfonate.
 4. A process according to claim 3 wherein saidsalt is SAMe disulfate tosylate.
 5. A process according to claim 1wherein said solutions are aqueous solutions.
 6. A process according toclaim 1 wherein the solution of the water-soluble salt of SAMe (A) has aconcentration from 10 to 25% by weight, preferably from 15 to 20% byweight.
 7. A process according to claim 1 wherein the coating agent (B)is selected from the group comprising chitins, carragenins, celluloseand chemically modified celluloses, gum or xanthane.
 8. A processaccording to claim 7 wherein the coating agent (B) is ahydroxypropylmethylcellulose.
 9. A process according to claim 1 whereinthe solution of the coating agent (B) has a concentration from 5 to 15%by weight, preferably from 7 to 10% by weight.
 10. A process accordingto claim 1 wherein the fluid bed granulation carrier (C) is selectedamong starch, cellulose and maltodextrin, preferably said carrier ismicrocrystalline cellulose.
 11. A process according to claim 1 whereinthe fluid bed granulation carrier (C) is characterized by a granulometryfrom 50 to 500μ, preferably from 100 to 200%.
 12. A process according toclaim 1 characterized by comprising an additional coating step with agastro-resistant coating agent.
 13. A granulate obtainable according tothe process of claim
 1. 14. A granulate, according to claim 13,comprising up to 60% by weight, preferably from 48 and 55% by weight, ofa water-soluble salt of SAMe (A), 5-15% by weight of a coating agent (B)and 25-45% by weight of carrier (C).
 15. Oral pharmaceuticalcompositions containing a granulate according to claim 13.